Type I interferons (IFNs) (IFN-.alpha. IFN-.beta. and IFN-.omega.) constitute a family of structurally related cytokines, usually defined by their ability to confer resistance to viral infections. Many other biological activities of type I IFNs have been reported, including inhibition of cell proliferation, induction of class I MHC antigens and several other immuno-regulatory activities (1). IFN-.alpha. and IFN-.beta. are useful for the treatment of several viral diseases, including hepatitis-C (2,3) and viral warts (4,5), as well as certain malignancies such as hairy cell leukemia (6), chronic myelogenous leukemia (7) and Kaposi's sarcoma (8).
IFN-.alpha. was detected in sera of various patents having autoimmune diseases such as systemic lupus erythematosus (9), as well as AIDS patients (10). IFN-.alpha. was implicated in the progression of juvenile diabetes (11). Further, IFN-.alpha. therapy has been shown in some cases to lead to undesired side effects, including fever and neurological disorders (12). Hence there are pathological situations in which neutralization of IFN-.alpha. activity may be beneficial to the patient.
As in the case of other cytokines, IFN-.alpha. exerts its biological activities by binding to a cell surface receptor, which is specific for all IFN-.alpha. subtypes, as well as for IFN-.beta. (13). A human IFN-.alpha. receptor (IFNAR) was identified and cloned from Daudi cells (14). The cloned receptor has a single transmembrane domain, an extracellular and an intracellular domain. When expressed in murine cells, this receptor confers responsiveness to human IFN-.alpha.B but not significantly to other IFN-.alpha. and IFN-.beta. species, indicating that additional components may be involved in the response to IFN-.beta. and to various IFN-.alpha. subtypes.
Several other studies indicate that there are additional components or receptor subunits involved in the binding of IFN-.alpha. and IFN-.beta. (15-17). Nevertheless, it was reported that the already described receptor (14) is involved in binding of all IFN-.alpha. and IFN-.beta. species (18). Indeed, a second receptor component, named IFN-.alpha./.beta. receptor was recently identified and cloned (EP publication No. 676,413 and ref. 19). We demonstrated that IFN-.alpha./.beta. receptor whose extracellular domain has the same sequence as IFNAB-BPI is the primary ligand-binding component of the Type I interferon receptor. Furthermore, interferon-.alpha./.beta. receptor and IFNAR cooperate in ligand-binding and form a ternary complex with Type I interferons on cell surface (20).
Monoclonal antibodies directed against IFNAR and capable of blocking the activity of Type I interferons in a non-selective manner were already described (21). Another monoclonal antibody, directed against an unidentified receptor component was described. This antibody blocked the activity of Type I interferons in a non-selective manner (22).